Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide

Tuberculosis (TB) remains among the world’s great public health challenges.Worldwide resurgence of TB

is due to two major problems: the AIDS epidemic, which started in the mid-1980s, and the outbreak of

multidrug resistant (MDR) TB. Thus, there is an urgent need for anti-TB drugs with enhanced activity

against MDR strains. In recent years, Schiff bases of 1H-indole-2,3-diones are reported to exhibit anti-TB

activity. On the other hand, several quinolone antibacterial agents have been examined as inhibitors of

TB, as well as other mycobacterial infections. Accordingly, the current work involved design and

synthesis of Schiff bases of nalidixic acid carbohydrazide and isatin derivatives (5,6aef and 7,8aec).

Structures of the synthesized derivatives were confirmed on the bases of spectral methods of analyses.

Anti-TB activity of the synthesized derivatives was investigated against four Mycobacterium strains:

Mycobacterium intercellulari, Mycobacterium xenopi, Mycobacterium cheleneo and Mycobacterium smegmatis.

Modest anti-TB activity was observed within the investigated compounds, however, compound 5f

revealed potent anti-TB activity with MIC 0.625 mg/ml, which is 20 times greater than the reference drug

isoniazid, INH, (MIC ¼ 12.5 mg/ml). A hypothetical pharmacophore model was built using Molecular

Operating Environment (MOE) program and 10 compounds structurally related to the synthesized ones

with reported anti-TB activity. The Pharmacophoric model built revealed the necessity of the following

pharmacophoric features for anti-TB activity: aromatic center, hydrogen bond acceptor/metal ligator

center, hydrogen bond donor center and aromatic center/hydrophobic area. Theses features were

consistent with the found anti-TB activity of the tested compounds.

Dr. Faizah Binjubair